WO2009024825A1 - Dérivés de 2-pyrazinylbenzimidazole en tant qu'inhibiteurs des récepteurs tyrosine kinase - Google Patents

Dérivés de 2-pyrazinylbenzimidazole en tant qu'inhibiteurs des récepteurs tyrosine kinase Download PDF

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WO2009024825A1
WO2009024825A1 PCT/GB2008/050726 GB2008050726W WO2009024825A1 WO 2009024825 A1 WO2009024825 A1 WO 2009024825A1 GB 2008050726 W GB2008050726 W GB 2008050726W WO 2009024825 A1 WO2009024825 A1 WO 2009024825A1
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alkyl
piperidin
ethyl
piperazin
amino
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PCT/GB2008/050726
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Bernard Christophe Barlaam
Claudio Edmundo Chuaqui
Benedicte Delouvrie
Gilles Ouvry
Tao Wang
Jon James Gordon Winter
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009024825A1 publication Critical patent/WO2009024825A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention concerns certain novel pyrazine derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also concerns processes for the manufacture of said pyrazine derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of cancers in a warm-blooded animal such as man, including use in the prevention or treatment of solid tumour disease.
  • Receptor tyrosine kinases are cell surface receptors that transmit signals from the extracellular environment to control growth, differentiation and survival of cells. All RTKs contain an extracellular ligand binding domain and a conserved protein tyrosine kinase cytoplasmic domain. RTKs are activated by growth factors, which promote receptor dimerisation and autophosphorylation of tyrosine residues in the kinase domain (Schlessinger, Cell, 2000, 103, 211).
  • RTKs can be classified into distinct subfamilies on the basis of sequence similarities.
  • the AxI receptor subfamily is one of these subfamilies and includes AxI (also called Ark and Ufo), Tyro3 (also called Rse, Brt and Sky) and Mer (also called Nyk and Tyro 12).
  • This RTK family is characterized by an extracellular domain consisting of two immunoglobulin-like and two fibronectin type 3 -like domains.
  • the AxI family RTKs are activated by the vitamin K-dependent protein known as growth arrest specific gene 6 (Gas6).
  • the affinity of Gas6 for these receptors is Axl>Tyro3>Mer (Nagata et al, J. Biol. Chem., 1996, 271, 30022).
  • the gene encoding for the AxI protein was originally identified as a transforming gene in chronic myeloid leukemia (O 'Bryan et al., MoI. Cell. Biol., 1991, 11, 5031).
  • the AxI receptor has been shown to be overexpressed in primary colon (Craven et al, Int. J. Cancer., 1995, 60, 791), gastric (Sawabu et al., MoI.
  • Gas6/Axl signalling has been shown to have roles in proliferation, protection from apoptosis, angiogenesis and invasion.
  • the gene encoding for AxI has been shown to transform both NIH-3T3 fibroblasts, enabling them to grow as xenografts in nude mice (O 'Bryan et al, MoI. Cell. Biol, 1991, 11, 5031), and IL-3 dependent hematopoietic 32D cells, enabling IL-3 independent growth (McCloskey et al, Cell Growth Differ., 1994, 5, 1105).
  • Gas6/Axl signalling has also been shown to have a weak mitogenic effect in mouse NIH-3T3 fibroblasts (Goruppi et al, Oncogene, 1996, 12, 471), human C57MG mammary carcinoma cells (Goruppi et al, MoI Cell Biol, 2001, 21, 902) and human DU 145 and PC3 prostate carcinoma cells (Sainaghi et al, J. Cell. Physiol, 2005, 204, 36).
  • AxI protein has been shown to disrupt CL 1-5 human lung adenocarcinoma cell invasion (Shieh et al, Neoplasia, 2005, 7, 1058) and primary human umbilical vein endothelial cells (HUVEC) cell migration and tube formation (Holland et al, Cancer Res., 2005, 65, 9294). Furthermore, inhibition of the AxI protein by either knockdown of protein levels (Holland et al, Cancer Res., 2005, 65, 9294) or transfection of a dominant negative AxI mutant gene (Vajkoczy et al, Proc. Natl. Acad. ScL USA, 2006, 103, 5799) has been shown to suppress xenograft growth in vivo.
  • AxI RTKs have also been shown to have roles in immunity (Lu et al, Science, 2001, 293, 306), platelet function (Angelillo-Scherrer et al, Nat. Med., 2001, 7, 215), spermatogenesis (Lu et al, Nature, 1999, 398, 723), vascular calcification (Son et al, Eur. J. Pharmacol, 2007, 556, 1), thrombin induced vascular smooth muscle cell (VSMC) proliferation (Nakano et al, J. Biol.
  • kidney diseases for example acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Yanagita et al, J. Clin. Invest., 2002, 110, 239).
  • antagonism of the activity of AxI receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer (comprising solid tumours such as carcinomas, sarcomas and the leukaemia and lymphoid malignancies), as well as vascular disease (including but not limited to thrombosis, atherosclerosis and restenosis), kidney disease (including but not limited to acute and chronic glomerulonephritis, diabetic nephropathy and transplant rejection), endometriosis, and diseases where deregulated angiogenesis is important (including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma).
  • cancer comprising solid tumours such as carcinomas, sarcomas and the leukaemia and lymphoid malignancies
  • vascular disease including but not limited to thrombosis,
  • c-Met is also a receptor tyrosine kinase which acts as the cellular receptor for hepatocyte growth factor (HGF/ scatter factor), a dimeric glycoprotein that is synthesized as a single-chain precursor called pro-HGF and comprises a 50 kDa ⁇ -chain and a 145 kDa ⁇ -chain.
  • HGF/ scatter factor hepatocyte growth factor
  • pro-HGF hepatocyte growth factor
  • c-Met activity is required for signal transmission via several signalling pathways.
  • c-Met-Gabl-Shp2 association results in sustained stimulation of the Erk pathway, thus stimulating cell transformation and proliferation (Maroun, C, et al. (2000), MoI. Cell. Biol. 20, 8513-8525; Schaeper, U, et al. (2000), J. Cell.
  • c-Met The role of c-Met on these different pathways, means that it is involved in the regulation of a range of different cellular processes such as proliferation, apoptosis, morphogenesis, and migration ⁇ Bardelli, A., et al. (1999) Oncogene 18, 1139-1146).
  • c-Met and HGF are expressed in numerous tissues. c-Met expression is normally restricted to cells of endothelial and epithelial origin. HGF is usually expressed in cells of mesenchymal origin and is therefore considered to be a paracrine acting growth factor which induces proliferative, morphogenic and motile responses in proximal target cells (Birchmeier, C, et al. (2003), Nature Rev. MoI. Cell. Biol. 4, 915-925).
  • c-Met activation promotes tumour growth and metastatic spread.
  • Activation of c-Met in cancer cells is most commonly driven by ligand-dependent mechanisms, for example, tumour carcinoma or tumour endothelial cells express c-Met but not HGF, which is produced by the surrounding stroma.
  • tumour carcinoma or tumour endothelial cells express c-Met but not HGF, which is produced by the surrounding stroma.
  • cells may express c-Met and HGF resulting in autocrine c-Met activation.
  • Ligand independent activation is also possible and is observed in cells that express very high levels of c-Met or which harbour activating mutations (Birchmeier et al.).
  • Activating mutations of c-Met have been discovered in sporadic and inherited forms of human renal papillary carcinoma (reviewed in Maulik et al. and Danilkovitch-Miagkova et al.) and, at present, 21 mutations have been described. The majority are localised within the kinase domain and are believed to convert c-Met into a constitutively active form. More recently, a number of additional mutations have been found in other types of primary cancer and metastatic lesions (Lorenzato, A., et al. (2002), Cane. Res. 62, 7025-7030).
  • mice expressing c-Met or HGF as a transgene in specific tissues ultimately develop a broad array of aggressively invasive tumours and metastatic lesions ⁇ Wang, R., et al. (2001), J. Cell Biol. 153, 1023-1034; Gallego, M.,et al. (2003), Oncogene 22, 8498-8508; and Takayama, K, et al. (1997), Proc. Natl. Acad.
  • c-Met therefore represents an attractive target in the pursuit of therapies for the treatment of cancer, and an inhibitor of c-Met activity would be expected to have anti- tumour activity and in particular anti-proliferative, anti-angiogenic and anti-invasive properties. Additionally, the role of c-Met and HGF in tissue remodelling, particularly in the lungs and liver has also been demonstrated ⁇ Michalopoulos, G. & DeFrances, M.
  • pyrazine derivatives possess potent activity against cell proliferative disorders.
  • the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on one or two biological processes, it is believed that the compounds provide a useful treatment of cell proliferative disorders, for example to provide an anti- tumour effect, by way of a contribution from inhibition of AxI and/or c-Met receptor tyrosine kinases.
  • each of Gi and G 2 is selected from CH and N provided that both are not N;
  • Ring A is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 1 is a group of the formula: R 5 -X !
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 6 ), CO, CH(OR 6 ), CON(R 6 ), N(R 6 )C0, N(R 6 )CON(R 6 ), SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, OC(R 6 ) 2 , C(R 6 ) 2 S, SC(R 6 ) 2 , C(R 6 ) 2 , C(R 6 ) 2 N(R 6 ) and N(R 6 )C(R 6 ) 2 , wherein each R 6 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and R 5 is amino-(l-6C)alkyl, (l-6C)alkyl,
  • Q 2 X 2 wherein X 2 has any of the meanings defined hereinbefore and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl or (3-8C)cycloalkyl-(l-6C)alkyl wherein any aryl or (3-8C)cycloalkyl group within a R 1 substituent bears 1 , 2 or 3 substituents independently selected from amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 9 )-amino-(l-6C)alkyl and di-(R 9 )-amino-(l-6C)alkyl, wherein R 9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy; m
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also
  • (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only.
  • (l-6C)alkoxy includes (3-6C)cycloalkyloxy groups and cycloalkyl-alkoxy groups having 4 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2- cyclobutylethoxy and cyclopentylmethoxy;
  • (l-6C)alkylamino includes (3- 6C)cycloalkylamino groups and 7V-(cycloalkylalkyl)amino groups having 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino,
  • (l-4C)alkyl refers to any of the alkyl groups defined above that posseses 1 to 4, 1 to 3 and 1 to 2 carbon atoms respectively.
  • the same convention applies to other terms used herein, such as, for example, "(l-4C)alkoxy”, “(1- 3C)alkoxy” and "(l-2C)alkoxy”.
  • heterocyclyl is to be understood as being, for example, a non-aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro- 1 ,4-thiazinyl, 1 , 1 -dioxotetrahydro- 1 ,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1
  • heteroaryl is to be understood as being, for example an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • a suitable value for Ring A when it is a 5- or 6-membered monocyclic or a 9- or 10- membered bicyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalin
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur and a suitable value for Ring A is, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl.
  • Ring A is a pyrazolyl or pyridinyl ring. In a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl or pyridin-3-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazolyl ring. In yet a further particular group of compounds of the Formula I, Ring A is a pyrazol-4-yl ring.
  • a suitable value for the heterocyclyl group within the R 1 group is, for example, a non-aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1- dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, qui
  • heterocyclyl ring When Q 1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl and especially piperidin- 4-yl and piperazin-1-yl.
  • heterocyclyl ring when Q 1 is an optionally substituted heterocyclyl or heterocyclyl-(l-6C)alkyl, particular examples of the heterocyclyl ring include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and especially piperidin-4-yl, piperidin-3-yl, piperazin-1-yl, morpholin-4-yl and tetrahydropyran-4-yl.
  • Q 1 comprises a heterocyclyl-(l-6C)alkyl substituent group on the heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl ring
  • particular values for the heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group include tetrahydrofuranyl, tetrahydropyranyl and especially tetrahydrofuran-4-yl or tetrahydropyran-4-yl.
  • a suitable value for the heteroaryl group within the R 1 or R 4 group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,
  • R 4 contains an optionally substituted heteroaryl or heteroaryl-(l-6C)alkyl group
  • heteroaryl ring include isoxazolyl and especially isoxazol-3-yl.
  • a suitable value for the aryl group within any R 1 or R 4 group is, for example, phenyl or naphthyl, conveniently phenyl.
  • a suitable value for the (3-8C)cycloalkyl group within any R 1 group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or cyclooctyl.
  • a suitable value for a heterocyclyl-(l-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl.
  • the invention comprises corresponding suitable values when, for example, rather than a heterocyclyl-(l-6C)alkyl group, a heteroaryl-(l-6C)alkyl, an aryl-(l-6C)alkyl or a (3-8C)cycloalkyl-(l-6C)alkyl group is present.
  • a suitable value for any heterocyclyl group within the R 3 or R 4 group is, for example, a non-aromatic saturated or partially saturated 3 to 12 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur. It is to be understood that the definition of heterocyclyl includes bridged ring systems.
  • Suitable examples include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1- dioxotetrahydrothiopyranyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, 1,1- dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, 2-azabicyclo[2.2.1]heptyl, qui
  • a particular example of a heterocyclyl ring within the R 4 group is, for example, tetrahydrofuranyl and especially tetrahydrofuran-3-yl.
  • the heterocyclyl ring within the R 4 group is, for example, tetrahydrofuranyl or pyrrolidinyl and especially tetrahydrofuran-3-yl or pyrrolidin-3-yl.
  • Suitable values for any of the 'R' groups (R 1 to R 4 ), or for various groups such as R 5 to R 9 within an R 1 substituent or for various groups such as R 10 within a R 3 group and R 1 ⁇ within a R 4 group include, for example :-
  • TV-methyl-TV' ,TV' -diethylureido for TV-(I -6C)alkylsulphamoyl: TV-methylsulphamoyl and TV-ethylsulphamoyl; io for TV,TV-di-[(l-6C)alkyl]sulphamoyl: TV,TV-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphony lamino ; for TV-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino : TV-methylmethanesulphonylamino and
  • TV-methy lethanesulphony lamino is for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl and 5- aminopropyl; for ( 1 -6C)alkylamino-( 1 -6C)alkyl: methylaminomethyl, ethylaminomethyl,
  • an R 1 group forms a group of the formula R 5 - X 1 - and, for example, X 1 is a OC(R 6 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 6 ) 2 linking group which is attached to Ring A and the oxygen atom is attached to the R 5 group.
  • an R 1 group forms a group of the formula Q 1 X 2 or of the formula Q 2 X 2 and, for example, X 2 is a OC(R 8 ) 2 linking group, it is the oxygen atom of the OC(R 8 ) 2 linking group which is attached to the Q 1 or Q 2 group.
  • a suitable value for an (R 7 )-amino-(l-6C)alkyl group or an (R 9 )-amino-(l-6C)alkyl group is, for example, trifluoromethylaminomethyl, cyanomethylaminomethyl, 2-cyanoethylaminomethyl, 2-hydroxyethylaminomethyl, 2- methoxyethylaminomethyl, 2-trifluoromethylaminoethyl, 2-(2-hydroxyethylamino)ethyl and 2-(2-methoxyethylamino)ethyl.
  • a suitable value for a di-(R 7 )-amino-(l- 6C)alkyl group or an di-(R 9 )-amino-(l-6C)alkyl group is, for example, di-(2- hydroxyethyl)aminomethyl and di-(2-methoxyethyl)aminomethyl.
  • a suitable value for a (R 10 ) p -(l-8C)alkyl group is, for example, chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2- difiuoroethyl, 2,2,2-trifluoroethyl, 3-fiuoropropyl, 3-chloropropyl, 3,3-difiuoropropyl, 3,3,3-trifluoropropyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2- hydroxyethyl, 3-hydroxypropyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3- methoxypropyl, 2-aminoethyl, 3-aminopropyl, 5-aminopropyl, 2-methylaminoethyl, 2- ethylamin
  • a suitable value for a (R 10 ) p -(2-8C)alkynyl group is, for example, A- dimethylaminobut-2-ynyl and 4-(heterocyclyl)but-2-ynyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic or citric acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dime thy lamine, trimethylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I. It is further to be understood that a suitable pharmaceutically-acceptable solvate of a compound of the Formula I also forms an aspect of the present invention.
  • a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I also forms an aspect of the present invention.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I. Accordingly, the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof.
  • the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-hvXy ⁇ , (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxyethyl est
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-( ⁇ - 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l-4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, 7V-ethyl-7V-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (l-4C)alkylamine such as methylamine
  • a di-(l-4C)alkylamine such as dimethylamine, 7V-ethyl-7V-methylamine or diethylamine
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • novel compounds of the invention include, for example, pyrazine derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Gi, G 2 , Ring A, m, n, R 1 , R 2 , R 3 and R 4 has any of the meanings defined hereinbefore or in paragraphs (a) to (iii) hereinafter: -
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • Ring A is a 5- membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is a 5- membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is a 6- membered monocyclic heteroaryl ring with up to three nitrogen atoms;
  • Ring A is furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
  • Ring A is pyrazolyl or pyridinyl; (1) Ring A is pyrazol-4-yl or pyridin-3-yl;
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl,s wherein any heterocyclyl or heteroaryl group within a R 8 ,
  • Q 2 X 2 wherein X 2 has any of the meanings defined hereinbefore and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl or (3-8C)cycloalkyl-(l-6C)alkyl wherein any aryl or (3-8C)cycloalkyl group within a R 1 substituent bears 1 , 2 or 3 substituents independently selected from amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (R 9 )-amino-(l-6C)alkyl and di-(R 9 )-amino-(l- 6C)alkyl, wherein R 9 is (l-6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy;
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substitu
  • R 1 is a group of the formula:
  • R ⁇ X 1 - wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO, SO 2 N(R 6 ), N(R 6 )SO 2 , C(R 6 ) 2 O, OC(R 6 ) 2 , C(R 6 ) 2 , C(R 6 ) 2 N(R 6 ) and N(R 6 )C(R 6 ) 2 , wherein each R 6 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and R 5 is amino-(l-6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substitu
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 , 2 or 3 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)
  • R 1 is a group of the formula:
  • X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )C0,
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy,
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-3C)alkyl, heteroaryl, heteroaryl-(l-3C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substituent optionally bears 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy
  • R 1 is a group of the formula:
  • X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO,
  • R 7 is (l-6C)alkyl; or R 1 is a group of the formula:
  • Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within a R 1 substituent optionally bears a halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, halogeno-(l-6C)alkyl, amino-(l-6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[( 1 -6C)alkyl] amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, TV-(I -6C)alkylcarb
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl,
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R 1 is aminomethoxy
  • R 1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1 -(l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), 1 -[I -(2-hydroxyethyl)piperidin-4-yl], l- ⁇ l-[2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6- (4-methylpiperaz
  • each R 2 group may be the same or different, and each R 2 group present is selected from halogeno, cyano, hydroxy, amino, (1- 8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2- 6C)alkynyloxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (1-
  • 6C)alkylsulphonyl (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, N-(l-6C)alkylcarbamoyl, N,N-di-[( ⁇ - 6C)alkyl]carbamoyl and (2-6C)alkanoylamino;
  • (aa) m is 0 or 1, and when m is 1, the R group present is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2- 6C)alkenyloxy, (2-6C)alkynyloxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (1- 6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(l-6C)alkyl]carbamoyl and
  • R 3 is hydrogen, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (R 10 ) p -(l-8C)alkyl, wherein each p is 1, 2 or 3 and each R 10 which may be the same or different, is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, wherein said heterocyclyl group optionally bears 1, 2 or 3 substituents independently selected from halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl, (2-8C)alkenyl, (2- 8C)alkynyl and (l-6C)alkoxy; (ff) R 3 is hydrogen, (l-8C)alkyl
  • R 4 is selected from hydrogen, fluoro, chloro, amino, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy;
  • n 0 or n is 1 and R 4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is a group of the formula:
  • X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO,
  • R 6 is hydrogen or (l-8C)alkyl; and R 5 is amino-(l-3C)alkyl, (l-6C)alkylamino-(l- 3C)alkyl, di-[(l-6C)alkyl]amino-(l-3C)alkyl, (R 7 )-amino-(l-3C)alkyl, di-[(R 7 )-amino-(l-
  • R 7 is (l-6C)alkyl; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • 6C)alkyl halogeno-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, ( 1 -6C)alkylamino-( 1 -6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethy
  • each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmethoxy or 2-phenylethoxy;
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • (yy) Ring A is pyrazolyl;
  • (zz) Ring A is pyrazol-4-yl;
  • Ring A is pyridin-3-yl or pyridin-4-yl;
  • Ring A is pyrazol-4-yl, R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl,
  • R 1 is 1 -(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1- ( l-ethylpiperidin-4-yl), 1 -(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4- yl], 1 - ⁇ 1 -[2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4- yl ⁇ , l-[2-(morpholin-4-yl)ethyl], 1 -(piperidin-4-ylmethyl), 1 -(piperidin-3-ylmethyl), 1 -(piperidin-3-yl), 1 -(tetrahydropyran-4-yl) or l-(4-a
  • R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l- yl), 6-(4-methylpiperazin-l-yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4- methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1 group is located at the stated 5- or 6- position on the pyridin-3-yl ring), and when Ring A is pyridin-4-yl, R 1 is 2-(piperazin-l-yl); (ddd) When Ring A is pyrazol-4-yl, R 1 is l-(piperidin-4-yl), l-(l-
  • (fff) m is 0 or 1 , and when m is 1 , the R group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl;
  • n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3-ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isoxazol-3-ylmethoxy or cyclopropylmethoxy; or (iii) n is 0 or 1 and, when n is 1, R 4 is selected from hydrogen, fluoro, oxolan-3- ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy.
  • a particular compound of the invention is selected
  • Gi and G 2 are both CH or Gi is N and G 2 is CH;
  • Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and Q 1 is heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, wherein any heterocyclyl or heteroaryl group within a R 1 substitu
  • Q 2 X 2 wherein X 2 has any of the meanings defined hereinbefore and Q 2 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl or (3-8C)cycloalkyl-(l-6C)alkyl wherein any aryl or (3-8C)cycloalkyl group within a R 1 substituent bears 1 , 2 or 3 substituents independently selected from amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l- 6C)alkyl, (R 9 )-amino-(l-6C)alkyl and di-(R 9 )-amino-(l-6C)alkyl, wherein R 9 is (1- 6C)alkyl substituted by 1, 2 or 3 substituents independently selected from halogeno, cyano, hydroxy and (l-6C)alkoxy;
  • R 11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C)alkyl, heteroaryl or heteroaryl-(l-6C)alkyl, wherein any aryl, heterocyclyl or heteroaryl group within the definition of R 11 optionally bears 1, 2 or 3 substituents independently selected from halogeno, trifluoromethyl, oxo, cyano, hydroxy, amino, carboxy, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Gi and G 2 are both CH or Gi is N and G 2 is CH; Ring A is a 5- or 6-membered monocyclic heteroaryl ring with up to three nitrogen atoms; R 1 is a group of the formula:
  • R ⁇ X 1 - wherein X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO, SO 2 N(R 6 ), N(R 6 )SO 2, C(R 6 ) 2 O, OC(R 6 ) 2, C(R 6 ) 2 , C(R 6 ) 2 N(R 6 ) and N(R 6 )C(R 6 ) 2 , wherein each R 6 is hydrogen, (l-8C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl or halogeno-(l-6C)alkyl, and R 5 is amino-(l-6C)alkyl,
  • R 1 is a group of the formula: Q 1 X 2 wherein X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N
  • R 3 is hydrogen, methyl, ethyl, propyl or (R 10 )-(l-3C)alkyl, wherein R 10 is selected from halogeno, cyano, hydroxy, (l-6C)alkoxy, amino, (l-6C)alkylamino, di-[(l-6C)alkyl] amino and heterocyclyl, wherein said heterocyclyl group optionally bears an halogeno, oxo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, ureido, (l-8C)alkyl,
  • R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazolyl or pyridinyl
  • R 1 is a group of the formula:
  • X 1 is a direct bond or is selected from O, SO 2 , N(R 6 ), CO, CON(R 6 ), N(R 6 )CO,
  • R 1 is (1 -6C)alkyl; or R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )CO, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl or piperazinyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-8C)alkyl,
  • R 3 is hydrogen, methyl, ethyl or propyl; n is O or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 1 ! , TV-(I -6C)alkylsulphamoyl, 7V,7V-di-[(l -6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, TV,TV-di-[(l- 6C)alkyl]carbamoyl and (2-6C)alkanoylamino, wherein R 11 is aryl, aryl-(l-6C)alkyl, heterocyclyl, heterocyclyl-(l-6C
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Gi and G 2 are both CH or Gi is N and G 2 is CH; Ring A is pyrazolyl or pyridinyl; R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: -
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazolyl or pyridinyl;
  • R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • (2-6C)alkanoyl TV-(I -6C)alkylcarbamoyl, (2-6C)alkanoylamino or heterocyclyl-(l- 6C)alkyl group, wherein said heterocyclyl within the heterocyclyl-(l-6C)alkyl substituent group is selected from tetrahydrofuranyl or tetrahydropyranyl; m is O or 1, and when m is 1, the R 2 group is selected from halogeno, cyano, hydroxy, amino, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, halogeno-(l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)al
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, 7V,7V-di-[(
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein: - Ring A is pyrazolyl or pyridinyl; R 1 is a group of the formula:
  • X 2 is a direct bond or is selected from O, SO 2 , N(R 8 ), CO, CON(R 8 ), N(R 8 )C0, SO 2 N(R 8 ), N(R 8 )SO 2 , C(R 8 ) 2 O, OC(R 8 ) 2 , C(R 8 ) 2 , C(R 8 ) 2 N(R 8 ) and N(R 8 )C(R 8 ) 2 , wherein each R 8 is hydrogen or (l-8C)alkyl, and Q 1 is heterocyclyl or heterocyclyl-(l-3C)alkyl, wherein said heterocyclyl or the heterocyclyl within the heterocyclyl-(l-3C)alkyl group is selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, each of which optionally bears a halogeno, oxo, trifluoromethyl, cyano, hydroxy,
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0 or 1 and when n is 1, R 4 is selected from hydrogen, halogeno, amino, cyano, sulphamoyl, OR 11 , /V-(l-6C)alkylsulphamoyl, /V,/V-di-[(l-6C)alkyl]sulphamoyl, trifluoromethyl, (l-8C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, halogeno-(l-6C)alkoxy, carbamoyl, TV-(I -6C)alkylcarbamoyl, /V,/V
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is suitably as defined in any one of paragraphs (e) to (1) above and is particularly as defined in any one of paragraphs (g) to (1) above;
  • R 1 is suitably as defined in any one of paragraphs (m) to (w) above and is particularly as defined in any one of paragraphs (q) to (w) above;
  • R 2 is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) above, and is particularly as defined in any one of paragraphs (gg) to (jj) above; and
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) above, and is particularly as defined in any one of paragraphs (nn) to (pp) above.
  • a yet further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 are suitably as defined in any one of paragraphs (a) to (d) above;
  • Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) above;
  • R 1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) above and is particularly as defined in any one of paragraphs (q) to (w) and (rr) to (uu) above;
  • R is suitably as defined in any one of paragraphs (x) to (dd) above, and is particularly as defined in any one of paragraphs (aa) to (dd) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) above;
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) above.
  • a yet further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 are suitably as defined in any one of paragraphs (a) to (d) and (xx) above;
  • Ring A is suitably as defined in any one of paragraphs (e) to (1) and (qq) and (yy) to (aaa) above and is particularly as defined in any one of paragraphs (g) to (1) and (qq) and (yy) to
  • R 1 is suitably as defined in any one of paragraphs (m) to (w) and (rr) to (uu) and (bbb) to
  • R 2 is suitably as defined in any one of paragraphs (x) to (dd) above and (fff), and is particularly as defined in any one of paragraphs (aa) to (dd) and (fff) above;
  • R 3 is suitably as defined in any one of paragraphs (ee) to (jj) and (w) and (ggg) above, and is particularly as defined in any one of paragraphs (gg) to (jj) and (w) and (ggg) above;
  • R 4 is suitably as defined in any one of paragraphs (kk) to (pp) and (ww) and (hhh) and (iii) above, and is particularly as defined in any one of paragraphs (nn) to (pp) and (ww) and (hhh) and (iii) above.
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazolyl or pyridinyl; R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, ethylaminomethyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, diethylaminomethyl, 2-(diethylamino)ethyl, 3-(diethylamino)propyl aminomethoxy, 2-(amino)ethoxy, 3-(amino)propoxy, methylaminomethoxy, 2- (methylamino)ethoxy, 3-(methylamino)propoxy, dimethylaminomethoxy
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazolyl or pyridinyl
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2-
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2-
  • R 4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, propxy, carbamoyl and acetamido, phenylmethoxy, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, oxolan-3-ylmethoxy, 2-(oxolan-3- yl)ethoxy or 3-(oxolan-3-yl)propoxy, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentyloxy
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is aminomethyl, 2-(amino)ethyl, 3-(amino)propyl, methylaminomethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, dimethylaminomethyl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl or pyridin-3-yl
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, l-[3-(oxan-4-yl)propyl]piperidin-4-yl, l-[2-(oxolan-3- yl)ethyl]piperidin-4-yl or l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, and when Ring A is pyridin-3-yl, R 1 is aminomethoxy, 2-(
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, 3-methoxypropyl, isobutyl, cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl, 2- (tetrahydrofuran-2-yl)ethyl or (3-methyloxetan-3-yl)methyl; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, chloro, amino, trifiuoromethyl,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; 30 Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -(3-hydroxypropyl)piperidin-4-yl, 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl]piperidin-4-yl, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, l-[2-(oxan-4- yl)ethyl]piperidin-4-yl, 1 -[3-(oxan-4-yl)propyl]piperidin-4-yl, 1 -[2-(oxolan-3- yl)ethyl]piperidin-4-yl, l-[3-(oxolan-3-yl)propyl]piperidin-4-yl]piperidin-4
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is located at the 1 position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- acetylpiperidin-4-yl, l-(2-hydroxyethyl)piperidin-4-yl, l-(3-hydroxypropyl)piperidin-4-yl, 1 - [2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - [3 -(tetrahydropyran-4- yl)propyl]piperidin-4-yl, l-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl, l-[2-
  • R 1 is located at the 5- or 6- position and is selected from 2-(amino)ethoxy, 3- (amino)propoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl),
  • R 3 is hydrogen; n is 0 or n is 1 and R 4 is selected from hydrogen, fluoro, methoxy, phenylmethoxy or oxolan-3-ylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-4-ylmethyl), l-(piperidin-3-ylmethyl)
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmeth
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l-methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin- 1 -yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin- 1 -y
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2-
  • R 1 is 6-[3- (dimethylamino)propoxy], 6-(piperidin-l-yl), 6-(piperazin-l-yl), 6-(4-methylpiperazin-l- yl), 5-(l -methylpiperidin-4-ylcarbamoyl), 5-[3-(4-methylpiperazin-l-yl)propylcarbamoyl] or 5-(4-methylpiperazin-l-ylcarbonyl) (that is each R
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, trifluoromethyl, methyl, chloro, bromo, (l-methylpyrrolidin-3-yl)oxy, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2-yl)methoxy, isopropoxy, ethoxy, (isoxazol- 3-ylmethoxy), cyclopentylmethoxy, cyclopropylmeth
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Ring A is pyrazol-4-yl
  • R 1 is l-(l-methylpiperidin-4-yl); m is 0; R 3 is hydrogen; n is 0; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazol-4-yl
  • R 1 is l-(l-methylpiperidin-4-yl) or l-(piperidin-4-yl); m is 0;
  • R 3 is hydrogen; n is 0; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi is CH and G 2 is N or Gi is N and G 2 is CH;
  • Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , l-[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-(tetrahydropyran-4-yl) or l-(4- aminocyclohex-1-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring), and when Ring
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, isobutyl, cyclopropylmethyl, 2- hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-ylmethyl or (3-methyloxetan-3- yl)methyl; n is 0, 1 or 2, and, when n is 2, each R 4 group present may be the same or different, and each R 4 group is selected from hydrogen, fluoro, methoxy, phenylmethoxy, oxolan-3- ylmethoxy, methyl, chloro, bromo, cyclopentyloxy, isobutoxy, (tetrahydrofuran-2- yl)methoxy, (isoxazol-3-ylmethoxy) or cyclopropylmethoxy; or a pharmaceutically- acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl, pyridin-3-yl or pyridin-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , 1 - ⁇ 1 -[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ , 1 -[2- (morpholin-4-yl)ethyl], l-(piperidin-3-yl), l-((piperidin-3-yl),
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or 1- (tetrahydropyran-4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fluoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; Ring A is pyrazol-4-yl or pyridin-3-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1- [2-(oxan-4-yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or 1- (tetrahydropyran-4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4- yl ring), and when Ring A is pyridin-3-yl, R 1 is 6-[3-(dimethylamino)propoxy], (that is each R 1 group is located at the stated 6- position on the pyri
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy and cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), 1-(1- ethylpiperidin-4-yl), l-(l-acetylpiperidin-4-yl), l-[l-(2-hydroxyethyl)piperidin-4-yl], 1- ⁇ 1-
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethylcyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from hydrogen, fiuoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the
  • Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Gi is CH and G 2 is N or Gi is N and G 2 is CH; Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :- Ring A is pyrazol-4-yl;
  • R 1 is l-(piperidin-4-yl), l-(l-methylpiperidin-4-yl), l-(l-ethylpiperidin-4-yl), 1-(1- acetylpiperidin-4-yl), 1 -[ 1 -(2-hydroxyethyl)piperidin-4-yl] , 1 - ⁇ 1 -[2-(oxan-4- yl)ethyl]piperidin-4-yl ⁇ , l- ⁇ l-[2-(oxolan-3-yl)ethyl]piperidin-4-yl ⁇ or l-(tetrahydropyran- 4-yl) (that is each R 1 group is located at the 1 -position on the pyrazol-4-yl ring); m is 0 or 1 , and when m is 1 , the R 2 group is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0 or 1, and, when n is 1, R 4 is selected from fiuoro, oxolan-3-ylmethoxy, (tetrahydrofuran-2-yl)methoxy or cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • a further particular compound of the invention is a pyrazine derivative of the
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R 1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 0; R 3 is hydrogen, methyl,
  • a further particular compound of the invention is a pyrazine derivative of the Formula I above wherein :-
  • Gi and G 2 is selected from CH and N provided that both are not N; Ring A is pyrazol-4-yl or pyridin-3-yl; When Ring A is pyrazol-4-yl, R 1 is located at the 1 -position and is selected from piperidin- 4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-(2- hydroxyethyl)piperidin-4-yl, 1 -[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl, 1 - (tetrahydrofuran-3-ylmethyl)piperidin-4-yl and tetrahydropyran-4-yl, and when Ring A is pyridin-3-yl, R 1 is located at the 6- position and is 3-(dimethylamino)propoxy; m is 1 , and R 2 is methyl;
  • R 3 is hydrogen, methyl, ethyl, propyl, 2-methoxyethyl, cyclopropylmethyl or 3- hydroxypropyl; n is 0, or, when each of Gi and G 2 is CH, n may be 1 and the (R 4 ) n group is selected from 5-fiuoro, 4-tetrahydrofuran-3-ylmethoxy, 4-[(tetrahydrofuran-2-yl)methoxy] and A- cyclopropylmethoxy; or a pharmaceutically-acceptable salt thereof.
  • Particular compounds of the invention are, for example, the pyrazine derivatives of the Formula I that are disclosed within the Examples that are set out hereinafter.
  • a particular compound of the invention is a pyrazine derivative of the
  • a further particular compound of the invention is a pyrazine derivative of the Formula I selected from any one of the following :-
  • a further particular compound of the invention is a pyrazine derivative of the
  • a yet further particular compound of the invention is a pyrazine derivative of the Formula I selected from any one of the following :-
  • Another aspect of the present invention provides a process for preparing a compound of the Formula I, or a pharmaceutically-acceptable salt thereof.
  • a suitable process is illustrated by the following representative process variants in which, unless otherwise stated, G 1 , G 2 , Ring A, R 1 , m, R 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • Suitable process variants include, for example, the following :- (a) The reaction of a carboxylic acid of the Formula II
  • G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, to provide an amide of the Formula IV
  • a suitable reactive derivative of a carboxylic acid of the Formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid with an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloro formate such as isobutyl chloro formate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafiuorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as methanol, ethanol, isopropanol, butanol or N- hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid with an azide such as diphen
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as N, ⁇ /-dimethylformamide, N,N
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C, conveniently at or near ambient temperature.
  • an active ester for example an ester formed by the reaction of the acid with an alcohol such as methanol, ethanol, isopropanol, butanol or tert- butanol
  • the reaction is conveniently carried out in the presence of a dipolar aprotic solvent such as 7V,7V-dimethylformamide or 7V,7V-dimethylacetamide at a temperature in the range, for example, 50 to 150 0 C, conveniently at or near 150 0 C.
  • a suitable base such as an alkali or alkaline earth metal (l-6C)alkoxide such as sodium methoxide is used.
  • a suitable acid for the cyclisation reaction is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide or, for example, an organic acid such as, for example, acetic acid or trifluoroacetic acid.
  • the reaction is conveniently carried out in the presence of a suitable solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, or a dipolar aprotic solvent as defined hereinbefore.
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 150 0 C, conveniently at or near 110 0 C.
  • Pyrazine carboxylic acids of the the Formula II, including reactive derivatives thereof such as an ester thereof may, for example, be prepared by the cross coupling reaction, conveniently in the presence of a suitable catalyst, of an organoboron reagent of the Formula V
  • R 2 L wherein each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom and Ring A, R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a pyrazine of the Formula VI
  • L is a displaceable group and L 3 is hydrogen or a protecting group such as methyl, whereafter any protecting group that is present is removed.
  • a suitable value for the ligands L 1 and L 2 which are present on the boron atom of the organoboron reagent include, for example, a hydroxy, (l-4C)alkoxy or (l-6C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand.
  • the ligands L 1 and L 2 may be linked such that, together with the boron atom to which they are attached, they form a ring.
  • L 1 and L 2 together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy, oxytrimethyleneoxy group or -O-C(CH 3 ) 2 C(CH 3 ) 2 -O- group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group.
  • Particularly suitable organoboron reagents include, for example, compounds wherein each of L 1 and L 2 is a hydroxy, a isopropoxy or an ethyl group or L 1 and L 2 together define a group of formula -O-C(CH 3 ) 2 C(CH 3 ) 2 -O-.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable catalyst for the cross coupling reaction includes, for example, a metallic catalyst such as a palladium(O), palladium(II), nickel(O) or nickel(II) catalyst, for example tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride or [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • a free radical initiator may conveniently be added, for example an azo compound such as azo(bisisobutyronitrile).
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • each of L 1 and L 2 which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • Pyrazine compounds of the Formula VII may be prepared, for example, by the cross coupling reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a pyrazine compound of the Formula IX wherein L is a displaceable group as defined hereinbefore and PG is a protecting group, with an organoboron reagent of the Formula V
  • R 2 L wherein each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter the protecting group PG is converted by way of a functional group interconversion into a displaceable group L.
  • a suitable protecting group PG is, for example, a methylthio group that may be converted to a methylsulphonyl group by oxidation with a suitable oxidising agent such as 3-chloroperbenzoic acid or a mixture of oxone and acetone, at a suitable temperature such as 0 to 100 0 C, and in a solvent such as tetrahydrofuran.
  • a suitable oxidising agent such as 3-chloroperbenzoic acid or a mixture of oxone and acetone
  • the protecting group PG is, for example, a hydrogen group that may be converted to a bromo group by brominating conditions such as phosphorous tribromide or 7V-bromosuccinimide, conveniently in the presence of a suitable base such as pyridine or triethylamine, in a suitable solvent such as methylene chloride and at a suitable temperature such as -30 to 100 0 C, conveniently at or near 30 0 C.
  • the protecting group PG is a displaceable group L as defined hereinbefore, in which case, provided that the organoboron reagent of the Formula V reacts selectively with the displaceable group that is located at the 4-position (relative to the amino group) in the pyrazine compound of the Formula IX, no conversion of the protecting group is necessary.
  • Organoboron compounds of the Formula VIII may be prepared by the reaction of a compound of the Formula X
  • L is a displaceable group as defined hereinbefore and G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a boron reagent, whereafter any protecting group that is present is removed.
  • L is a halgeno group such as a bromo or iodo group.
  • Synthetic procedures for forming heteroarylboron reagents from heteroaryl halides are well known in the art, for example, a 2-halogeno-substituted benzimidazole or azabenzimidazole compound of the Formula X may be reacted with a boron reagent such as bis(pinacolato)diboron or diborane, conveniently in the presence of a suitable base such as pyridine or triethylamine, in a solvent such as tetrahydrofuran and at a temperature in the range -10 to 75°C, conveniently in the range 0 to 30 0 C.
  • a boron reagent such as bis(pinacolato)diboron or diborane
  • a suitable base such as pyridine or triethylamine
  • a solvent such as tetrahydrofuran
  • L is a displaceable group as defined hereinbefore and G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula V
  • R 2 L wherein each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an alkali or alkaline earth metal fluoride, for example caesium fluoride, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • L is a displaceable group as defined hereinbefore, may be reacted with a 1 ,2- diamine of the Formula III
  • a carboxylic acid of the Formula XII and a 1,2-diamine of the Formula III may be reacted in the presence of an amide coupling reagent such as a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) or a carbodiimide such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, conveniently in the presence of an organic base such as pyridine or trie thy lamine, in a solvent such as N, ⁇ /-dimethylformamide and a temperature in the range of 0 to 150 0 C, conveniently at or near ambient temperature.
  • Cyclisation of the resultant amide product may conveniently be carried out in the presence of a suitable organic acid such as acetic acid and at a temperature in the range, for example, 0 to 150 0 C, conveniently at or near 100
  • compounds of the Formula XI may be produced by reacting a carboxylic acid, or a reactive derivative thereof as defined hereinbefore, of the Formula XIIa
  • a halogenating agent for example a brominating agent, such as for example bromine or N-bromosuccinimide to form a compound of the Formula XI, whereafter any protecting group that is present is removed.
  • a carboxylic acid of the Formula XIIa and a 1,2-diamine of the Formula III may be reacted in the presence of an amide coupling reagent such as a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) or a carbodiimide such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, conveniently in the presence of an organic base such as pyridine or trie thy lamine, in a solvent such as N, ⁇ /-dimethylformamide and a temperature in the range of 0 to 150 0 C, conveniently at or near ambient temperature.
  • an amide coupling reagent such as a uronium compound such as 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexaflu
  • Cyclisation of the resultant amide product to form a compound of the Formula XIa may conveniently be carried out in the presence of a suitable organic acid such as acetic acid and at a temperature in the range, for example, 0 to 150 0 C, conveniently at or near 100 0 C.
  • a suitable organic acid such as acetic acid
  • halogenation of compound XIa is suitably carried out in the presence of a solvent or diluent such as for example, N, ⁇ /-dimethylformamide, tetrahydrofuran, 1,4-dioxan, 1 ,2-dimethoxyethane, benzene, or halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example -50 0 C to 100 0 C, preferably in the range 0 0 C to 30 0 C.
  • a solvent or diluent such as for example, N, ⁇ /-dimethylformamide, tetrahydrofuran, 1,4-dioxan, 1 ,2-dimethoxyethane, benzene, or halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example -50 0 C to 100 0 C
  • Ring A, m, R 2 , Gi, G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, 7V-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, 7V-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as N, ⁇ /-dimethylformamide
  • Compounds of the Formula XIV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • Carboxylic acid starting materials of the Formula XV may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter. For example, using an analogous procedure to that described in process variant (c), a compound of the Formula XI
  • L is a displaceable group as defined hereinbefore and G 1 , G 2 , R J , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted, conveniently in the presence of a suitable catalyst as defined hereinbefore, with an organoboron reagent of the Formula XVI
  • R 2 L wherein each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • Compounds of the Formula XVI may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • Q 1 - NH(R S ) ⁇ v ⁇ wherein Q 1 and R 8 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the Formula XV or a reactive derivative thereof as defined hereinbefore, wherein Ring A, m, R 2 , G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, such as those defined hereinbefore for process variant (d).
  • a suitable inert solvent or diluent such as those defined hereinbefore for process variant (d).
  • the reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 0 C, preferably at or near ambient temperature.
  • Compounds of the Formula XVII may be obtained by conventional procedures such as those disclosed in the Examples that are set out hereinafter or they are commercially available, known in the literature, or they can be prepared by standard processes known in the art.
  • Q 1 is a heterocyclyl or heteroaryl group as defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium bicarbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • an alkali or alkaline earth metal carbonate or hydroxide for example sodium bicarbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic solvent such as toluene.
  • a dipolar aprotic solvent such as N, ⁇ /-dimethylformamide
  • L is a displaceable group as defined hereinbefore and G 1 , G 2 , R 3 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an organoboron reagent of the Formula XX wherein L is a displaceable group as defined hereinbefore and each of L 1 and L 2 , which may be the same or different, is a suitable ligand for the boron atom as defined hereinbefore and Ring A, R 1 , m and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • a suitable base such as an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • a suitable inert solvent or diluent for example 7V,7V-dimethylformamide, water, tetrahydrofuran, 1 ,4-dioxan, 1 ,2-dimethoxyethane, benzene, toluene, xylene, methanol or ethanol and at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 180 0 C.
  • Compounds of the Formula XI may be produced using procedures
  • the reaction is carried out in the presence of a mixture of an azo compound such as diethyl, diisopropyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example tetrahydrofuran or a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 80 0 C, preferably at or near ambient temperature.
  • Ring A, R 1 , m, R 2 , G 1 , G 2 , n and R 4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alkylating agent which also has any functional group protected if necessary, whereafter any protecting group that is present is removed.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example N, ⁇ /-dimethylformamide, 7V,A/-dimethylacetamide, N- methylpyrrolidin-2-one or a halogenated solvent such as dichloromethane.
  • the reaction is carried out in dimethylformamide, 7V, ⁇ /-dimethylacetamide or N- methylpyrrolidin-2-one and at a temperature in the range, for example, -10 0 C to 180 0 C, conveniently in the range 0 to 100 0 C, more conveniently at or near ambient temperature.
  • a suitable alkylating agent is, for example, a compound wherein a (l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, or heterocyclyl-(l-6C)alkyl group is attached to a suitable leaving group, for example a chloro, bromo, iodo, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable leaving group for example a chloro, bromo, iodo, methoxysulphonyloxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • alkylating agents examples include iodomethane, iodoethane, l-bromo-2-methyl-propane, bromomethylcyclopropane, 2-(2-bromoethoxy)-2-methyl-propane, 2-(3-bromopropoxy)-2- methyl-propane, 2-(bromomethyl)tetrahydrofuran and 3-(chloromethyl)-3-methyl-oxetane.
  • the reaction is conducted in the presence of a suitable base such as an alkali or alkaline earth metal carbonate, for example caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine or a base such as sodium hydride.
  • a suitable base such as an alkali or alkaline earth metal carbonate, for example caesium carbonate or potassium carbonate, or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or morpholine or a base such as sodium hydride.
  • a reductive amination reaction can be carried out to couple a compound of Formula I obtained by any of the processes described hereinbefore having a nitrogen containing heterocyclyl ring such as, for example, piperidin-4-yl as an R 1 group with a suitable aldehyde or ketone to obtain another compound of the Formula I, for example, if formaldehyde, or a equivalent thereof, is used, a compound of Formula I having a l-methylpiperidin-4-yl R 1 group may be obtained.
  • a suitable reducing agent for such a reductive amination reaction is, for example, a hydride reducting agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • a hydride reducting agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a suitable inert solvent or diluent for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a pharmaceutically-acceptable salt of a pyrazine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrazine derivative with a suitable acid.
  • a pharmaceutically-acceptable pro-drug of a pyrazine derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said pyrazine derivative with a suitable acid.
  • Formula I is required, it may be obtained using a conventional procedure.
  • an in vivo cleavable ester of a pyrazine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable alcohol or by reaction of a compound of the Formula I containing a hydroxy group with a pharmaceutically-acceptable carboxylic acid.
  • an in vivo cleavable amide of a pyrazine derivative of the Formula I may be obtained by, for example, reaction of a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable amine or by reaction of a compound of the Formula I containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • a compound of the Formula I containing a carboxy group with a pharmaceutically-acceptable amine or by reaction of a compound of the Formula I containing an amino group with a pharmaceutically-acceptable carboxylic acid.
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, acylation of substituents, amidation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • Certain of the intermediates defined herein are novel and these are provided as a further feature of the invention.
  • many compounds of the Formulae II, XI and XV are novel compounds.
  • the following assays can be used to measure the effects of the compounds of the present invention as inhibitors of AxI and cMet tyrosine kinase enzymes, as inhibitors in vitro of the phosphorylation of AxI expressed on NCI H 1299 lung large cell carcinoma cells and as inhibitors in vitro of the phosphorylation of cMet expressed on MKN45 cells.
  • the assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry. 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant AxI tyrosine kinase.
  • N-terminal GST-AxI kinase domain encompassing amino acids 473 to 894 of AxI was expressed in SF 126 insect cells and purified using the GST epitope tag, using standard purification techniques.
  • Test compounds were prepared as 1OmM stock solutions in dimethylsulphoxide (DMSO) and diluted in DMSO as required. Aliquots (12OnI) of compound dilutions were filled into the wells of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one) using acoustic dispensing (Labcyte Echo 550).
  • LV low volume
  • a 10 ⁇ l mixture of recombinant purified AxI enzyme, biotinylated peptide substrate Biotin poly-GAT;
  • CisBio Catalogue No. 6 IGATBLB
  • 0.2 ⁇ M adenosine triphosphate (ATP) and a buffer solution [comprising 20 mM Tris-HCl pH 7.5 buffer, 0.01% v/v Tween, 5 mM dithiothreitol (DTT) and 10 mM manganese chloride] was incubated with the compounds at room temperature for 20 minutes.
  • Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 100% DMSO instead of test compound.
  • Control wells that produced a minimum signal corresponding to 100% inhibited enzyme were created by adding 10 ⁇ M of a test compound.
  • This assay uses a conventional ELISA method to determine the ability of test compounds to inhibit phosphorylation of tyrosine residues in AxI.
  • NCI H 1299 lung large cell carcinoma cell line [American Type Culture Collection (ATCC) CRL 5803] was routinely maintained at 37°C with 5% CO 2 in RPMI containing 10% foetal calf serum (FCS) and 2mM L-glutamine.
  • FCS foetal calf serum
  • the cells were detached from the culture flask with 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT 104) using standard tissue culture methods and re- suspended in media to give 0.9xl0 5 cells per ml. lOO ⁇ l Aliquots were seeded into each of the wells of a clear 96 well tissue culture plate and the plates were incubated overnight at 37°C with 5% CO 2 to allow the cells to adhere to the wells.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required in DMSO to give a range of concentrations. Aliquots of each compound concentration were added to the cells in each well using the Echo 550 (Labcyte Inc.,
  • Control cells received DMSO only. The cells were incubated for 2 hours at 37°C with 5% CO 2 .
  • the resultant cells were stimulated with 100 ng/ml recombinant mouse GAS6 (RnD systems; Catalogue No. 986-GS) for 10 minutes at 37°C with 5% CO 2 .
  • Cells were lysed by the addition of 50 ⁇ l/well of lysis buffer comprising 2OmM Tris-HCl pH 8.0, 137 mM sodium chloride, 2 mM EDTA, 10% v/v glycerol, 1% v/v Igepal CA-630, 0.5mM sodium orthovanadate, 1 mM sodium pyrophosphate, 10 mM sodium pyrophosphate, 10 mM glycerophosphate and IX protease inhibitor tablets (Roche; catalogue number 11836153001).
  • the resultant tissue culture plates were incubated on ice for 30 minutes to ensure full lysis.
  • High-binding ELISA plates were coated with an anti-Axl antibody (RnD systems; Catalogue No. AF 154) at room temperature for 16 hours.
  • the wells were washed 3 times with 250 ⁇ l per well of PBS containing 0.05% v/v Tween (PBS/T).
  • the wells were treated with 3% w/v BSA in PBS at ambient temperature for 2 hours and subsequently washed 3 times with 250 ⁇ l per well of PBS/T.
  • the plates were washed 3 times with 250 ⁇ l per well of PBS/T. Fluorogenic substrate was made up according to manufacturers instructions (Pierce Biotechnology Inc., Rockford IL, USA; Catalogue No. 15169). 100 ⁇ l Aliquots of substrate solution were added to each of the wells and fluorescence was read on a Tecan Ultra plate reader (Tecan UK Ltd., Reading, Berkshire, UK). Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of phospho-Axl was expressed as an IC50 value. The IC50 value is the concentration of test compound that inhibits 50% of kinase activity.
  • the assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to prevent the activation of c-Met, in which wild type activated c-Met phosphorylates a mutant form of c-Met lacking catalytic activity but retaining the ability to be phosphorylated on the activating residues.
  • kinase activity assays were performed in 384-well low- volume white plates (Greiner, 784075) with a total volume of 12 ⁇ L in each well.
  • Each kinase reaction contained 40pg (10OpM) pY 1234 pY 1235 c-Met(1074-1366) kinase domain, 44ng (10OnM) cMyc-[D1204N,R1208Q]c-Met(1069-1366)-biotin, 25mM HEPES (pH7.4), 0.ImM sodium orthovanadate, ImM DTT, 0.01% (v/v) Tween-20, 1OmM Magnesium Chloride, 0.1% BSA, 50 ⁇ M ATP.
  • test compounds were each added in 6% (v/v) DMSO to yield a final assay DMSO concentration of 1% (v/v).
  • the kinase reactions were incubated at room temperature for 60 minutes and stopped by adding 5 ⁇ L containing 0.5ng anti- pYpY 1234/1235 c-Met rabbit polyclonal antibody (AstraZeneca Pharmaceuticals) with 200ng rabbit IgG Protein A Alphascreen acceptor beads (Perkin Elmer 6760617R) & 200ng streptavidin donor beads (Perkin Elmer 6760617R) in 25 mM HEPES (pH 7.4), 84.5mM EDTA, 0.3% BSA under low-level light conditions.
  • IC50 value is the concentration of test compound that inhibits 50% of c-Met kinase activity.
  • test compounds can be used to indicate the ability of a test compound to inhibit c-Met mediated cellular signalling in mammalian cell lines, for example the human tumour cell line MKN45. This is achieved by measuring the amount of phosphorylated c- Met within a cell following compound treatment.
  • MKN45 cells were routinely passaged in DMEM (Gibco BRL, product number 41966-029) plus 10% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, product number 25030024), to a confluence not greater than 85%.
  • FCS foetal calf serum
  • L-glutamine Gibco BRL, product number 25030024
  • MKN45 cells were seeded at 2xlO 4 cells/ well in DMEM plus 0.5% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, product number 3904) and incubated at 37°C (+5% CO 2 ) in a humidified incubator. Once the cells had fully adhered (typically following overnight incubation) plates were dosed with 25 ⁇ l compound (diluted from 10 mM stock in DMSO using serum free DMEM) and the plates were returned to a humidified 37°C (+5% CO 2 ) incubator for one hour. Following incubation the cells were fixed by adding formaldehyde (4% final concentration) and incubating at room temperature for 20 minutes.
  • the fixative solution was then removed and the wells were washed three times with 100 ⁇ l phosphate buffered saline (PBS) before permeabilising the cells by the addition of 50 ⁇ l/well 0.1% triton/ PBS for 20 minutes at room temperature.
  • the permeabilisation solution was then removed and the cells washed twice more with lOO ⁇ l/ well PBS before the addition of 40 ⁇ l/well anti-phospho pYpYpY 1230/4/5 c-Met (Biosource, product number 44-888G-CS2), diluted 1/500 with PBS plus 10% FCS.
  • the antibody solution was removed and the wells were washed twice with 100 ⁇ l/ well PBS.
  • Preferred compounds of the invention possess activity at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d) :-
  • the pyrazine compound disclosed within Example 1 possesses activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC50 versus cellular phospho-Axl of approximately 40 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 1.04 ⁇ M; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY 1230/4/5 ) of approximately 60 nM.
  • the pyrazine compound disclosed within Example 5 possesses activity in Test (a) with an IC 50 versus AxI tyrosine kinase of approximately 20 nM; and activity in Test (b) with an IC 50 versus cellular phospho-Axl of approximately 20 nM; and activity in Test (c) with an IC50 versus c-Met tyrosine kinase of approximately 0.48 ⁇ M; and activity in Test (d) with an IC50 versus cellular phospho-c-Met (pYpYpY 1230/4/5 ) of approximately 8O nM.
  • pyrazine compounds disclosed within the Examples possess activity in Test (b) at the levels illustrated in Table A.
  • Example 20 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.016 ⁇ M.
  • ** the compound disclosed in Example 22 had an activity in Test (a) with an IC50 versus AxI tyrosine kinase of approximately 0.002 ⁇ M.
  • Example 23 had an activity in Test (a) with an IC 50 versus AxI tyrosine kinase of approximately 0.003 ⁇ M.
  • a pharmaceutical composition which comprises a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixi
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • antagonism of the activity of AxI and/or c-Met receptor kinases is expected to be beneficial in the treatment of a number of cell proliferative disorders such as cancer.
  • novel pyrazine derivatives described herein possess potent activity against cell proliferative disorders. It is believed that the compounds provide a useful treatment of cell proliferative disorders, for example to provide an anti- tumour effect, by way of a contribution from inhibition of AxI and/or c-Met receptor tyrosine kinases.
  • AxI and c-Met are involved in angiogenesis, the process of forming new blood vessels that is critical for continuing tumour growth. It is therefore believed that the compounds of the present invention are expected to be beneficial in the treatment of a number of disease states that are associated with angiogenesis and/or increased vascular permeability such as cancer, especially in inhibiting the development of tumours.
  • Particular compounds of the invention possess better potency against AxI receptor tyrosine kinases than against c-Met receptor kinases.
  • a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prophylaxis) of cell proliferative disorders or in the treatment (or prophylaxis) of disease states associated with angiogenesis and/or vascular permeability there is provided the use of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prophylaxis) of cell proliferative disorders or in the treatment (or prophylaxis) of disease states associated with angiogenesis and/or vascular permeability.
  • a method for the treatment (or prophylaxis) of cell proliferative disorders in a warm-blooded animal in need of such treatment (or prophylaxis) or for the treatment (or prophylaxis) of disease states associated with angiogenesis and/or vascular permeability in a warm-blooded animal in need of such treatment (or prophylaxis) which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include neoplastic disorders, for example, cancers of the lung (non-small cell lung cancer, small cell lung cancer and bronchioalveolar cancer), gastrointestine (such as colon, rectal and stomach tumours), prostate, breast, kidney, liver, brain (such as glioblastoma), bile duct, bone, bladder, head and neck, oesophagus, ovary, pancreas, testes, thyroid, cervix and vulva and skin (such as dermato fibrosarcoma protruberans) and in leukaemias and lymphomas such as chronic myelogenous leukaemia (CML), chronic myelomonocytic leukaemia (CMML), acute lymphocytic leukaemia (ALL), chronic neutrophilic leukaemia (CNL), acute myelogenous leukaemia (AML) and multiple myeloma.
  • CML chronic myelogenous leukaemia
  • a method for treating cell proliferative disorders such as solid tumour disease
  • a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-accep table salt thereof, as defined hereinbefore.
  • Suitable cell proliferative disorders include non-malignant disorders such as blood vessel disease (for example atherosclerosis and restenosis, for example in the process of restenosis subsequent to balloon angioplasty and heart arterial by-pass surgery), fibrotic diseases (for example kidney fibrosis, hepatic cirrhosis, lung fibrosis and multicystic renal dysplasia), glomerulonephritis, benign prostatic hypertrophy, inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, allergic asthma, insulin- dependent diabetes, diabetic retinopathy, diabetic nephropathy and endometriosis.
  • non-malignant disorders such as blood vessel disease (for example atherosclerosis and restenosis, for example in the process of restenosis subsequent to balloon angioplasty and heart arterial by-pass surgery), fibrotic diseases (for example kidney fibrosis, hepatic cirrhosis, lung
  • Suitable disease states associated with angiogenesis and/or vascular permeability include, for example, the undesirable or pathological angiogenesis seen in diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma.
  • a pyrazine derivative of the Formula I or a pharmaceutically-accep table salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment (or prevention) of those tumours which are sensitive to inhibition of AxI and/or c-Met receptor enzymes that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
  • a method for the treatment (or prevention) of a warm-blooded animal having tumours which are sensitive to inhibition of AxI or c-Met receptor enzymes that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-accep table salt thereof, as defined hereinbefore.
  • a pyrazine derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing an AxI and/or c-Met receptor enzyme inhibitory effect.
  • a method for inhibiting an AxI and/or c-Met receptor enzyme which comprises administering an effective amount of a pyrazine derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithra
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as ⁇ /-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD 1839), ⁇ /-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI-774) and 6-acrylamido- ⁇ /-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family,
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a pyrazine derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of AxI or c-Met receptor tyrosine kinase enzymes. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • ⁇ ATU (2.16 g) was added to a mixture of triethylamine (1.13 ml), 4-fluoro-l,2- diaminobenzene (0.72 g) and 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (2.1 g) in DMF (25 ml) at ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with dilute aqueous sodium hydrogen carbonate solution. The precipiate was isolated by filtration and dried in a vacuum oven.
  • the 3 -amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4- yl)pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), methyl 3-amino-6-bromopyrazine-2-carboxylate (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (30.4 g) in methanol (450 ml) at ambient temperature.
  • 2M sodium hydroxide solution (8.70 ml) was added to a solution of methyl 3- i o amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxylate (3.5 g) in methanol (40 ml) and stirred at ambient temperature for 2 hours. The resultant solution was concentrated in vacuo until half of the methanol had been removed. Water (20 ml) was then added and the solution was acidified to pH4 by addition of 2M hydrochloric acid causing the product to precipitate. This material was filtered and dried is invacuo.
  • Methyl 3-amino-6-[l-(l-tert-butoxycarbonyl-piperidin-4-yl)pyrazol-4-yl]pyrazine- 2-carboxylate 8 g was dissolved in TFA (25 ml) and the mixture was stirred for 1 hour. The resultant mixture was concentrated under reduced pressure. The residue was purified by SCX ion exchange chromatography (eluted using 7M methanolic ammonia). The resulting compound was triturated with diethyl ether.
  • the 3-phenylmethoxybenzene-l,2-diamine used as a reagent to make compound [2] above was prepared as follows: Potassium carbonate (14.83 g) was added in one portion to 2-amino-3-nitrophenol (16.54 g) in ethanol (100 ml) at ambient temperature. The resulting mixture was stirred for 15 minutes. Benzyl chloride (16.05 ml) and sodium iodide (0.184 ml) were added to the reaction mixture and the resulting mixture was stirred at 78 0 C for 2 hours. The reaction mixture was evaporated to dryness and the residue was redissolved in ethyl acetate, and washed sequentially with water and saturated brine.
  • Ammonium formate (0.28 g) was added in one portion to tert-butyl 4-[4-[5-amino-6- (7-phenylmethoxy- lH-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.39 g) and palladium (0.072 g) in methanol (15 ml) at ambient temperature. The resulting suspension was stirred at 70 0 C for 8 hours. The reaction mixture was filtered through celite. The celite was washed with dimethylformamide (50 ml) and combined with the methanol filtrate.
  • Triphenylphosphine (0.028 ml) and diisopropyl azodicarboxylate (0.025 ml) were added in one portion to tert-butyl 4-[4-[5-amino-6-(7-hydroxy-lH-benzimidazol-2- yl)pyrazin-2-yl]pyrazol-l-yl]piperidine-l -carboxylate (0.050 g) and tetrahydrofuran-3- ylmethanol (0.012 ml) in tetrahydrofuran (1 ml) at ambient temperature. The resulting solution was stirred for 2 hours.
  • reaction mixture was then evaporated to dryness and redissolved in dichloromethane (1 ml), and trifiuoroacetic acid (1 ml) was added in one portion. The resulting solution was stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated to dryness and redissolved in DMSO (1.2 ml), and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% ammonia) and acetonitrile as eluents.
  • HATU 47.6 g was added to a stirred solution of 1 ,2-phenylenediamine (13.54 g), 3-amino-6-bromopyrazine-2-carboxylic acid (26.0 g) and triethylamine (24.93 ml) in DMF (250 mL).
  • the resulting solution was stirred at ambient temperature for 12 hours before the reaction mixture was added to water (250 ml).
  • the resulting precipitate was collected by filtration, washed with water (250 ml) and dried in vacuo. This material was dissolved in acetic acid (200 ml) and heated to 9O 0 C for 4 hours.
  • the reaction mixture was concentrated in vacuo, washed with diethylether.
  • tert-butyl 3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)methyl)piperidine-l-carboxylate was prepared from tert-butyl 3-
  • the product was obtained by reaction of 5-bromo-3-(5-fiuoro-lH-benzimidazol-2- yl)pyrazin-2-amine and l-(tetrahydropyran-4-yl)-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole according to Example 3 except that the reaction was run in DMA:water (4:1) at 150 0 C in a microwave oven for 30 min using caesium fluoride in place of sodium bicarbonate.
  • the product gave the following characteristising data: Mass Spectrum: M+H + 380.
  • the product was obtained by reaction of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate and 5-bromo-3-(5-chloro-6- fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine according to an analogous procedure to that described in Example 3 except that the reaction was carried out in dioxane using 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) as the catalyst and aqueous sodium carbonate as the base and the reaction mixture was heated to 100 0 C for 3 hours under microwave irradiation and the resultant intermediate was reacted with trifiuoroacetic acid.
  • 5-Bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine used as starting material was prepared from 3-aminopyrazine-2-carboxylic acid and 4-chloro-5- fluorobenzene-l,2-diamine as described in example 4.03, starting material: 3-amino-N-(2-amino-4-chloro-5-fluorophenyl)pyrazine-2-carboxamide (200 mg).
  • the 5-bromo-3-(5-chloro-6-fluoro-lH-benzimidazol-2-yl)pyrazin-2-amine gave the following characterising data; Mass Spectrum: M+H + 342
  • tert-butyl 4-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazol- 1 - yl)cyclohexylcarbamate used as starting material was prepared from tert-butyl N-(4- hydroxycyclohexyl)carbamate using the same sequence as described in Example 4.07.
  • Acetic acid (0.023 ml) was added to a solution of 3-(5-fluoro-lH-benzimidazol-2-yl)- 5-(l-piperidin-4-ylpyrazol-4-yl)pyrazin-2-amine (0.15 g) and formaldehyde (0.041 ml) in methanol (5 ml). The resultant mixture was stirred for 10 minutes at ambient temperature. Sodium cyanoborohydride (0.029 g) was added and the mixture was stirred for 1 hour at ambient temperature. The mixture was filtered, concentrated in vacuo and purified by SCX ion exchange chromatography, with the eluent 2M NH 3 /in methanol. The resultant solid was hen purified by preparative HPLC using decreasingly polar mixtures of water
  • Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to a mixture of ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.105 g), 3- (l//-benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.1 g) and 2M sodium bicarbonate (0.207 ml) in a solvent of 2:7:3:2 DMF:DME:ethanol:water (4 ml). The resulting mixture was stirred and heated to 160 0 C for 20 minutes. The residue was evaporated to afford 5- [5-amino-6-(lH-benzimidazol-2-yl)pyrazin-2-yl]pyridine-3-carboxylic acid.
  • Dichlorobis(triphenylphosphine)palladium(II) (0.012 g) was added to 3-(1H- benzimidazol-2-yl)-5-bromopyrazin-2-amine (0.100 g), 2-fluoropyridin-5-ylboronic acid (0.072 g) and 2M sodium bicarbonate (0.207 ml) in a mixture of 2:7:3:2 DMA:DME:ethanol:water (5 ml). The mixture was heated to 160 0 C for 40 minutes in a microwave. Piperidine (0.3 ml) was then added and the solution was heated to 120 0 C for a further 20 minutes. The crude product was purified by SCX ion exchange chromatography.
  • Diisopropyl azodicarboxylate (0.03 ml) was added to a solution of tert-butyl 4-[4-[5- i o amino-6-(7-hydroxy- 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 - carboxylate (0.06 g, triphenylphosphine (0.04 g), l-methylpyrrolidin-3-ol (0.015 g) in tetrahydrofuran (1.2 ml). The mixture was shaken for 4 days. The resultant mixture was concentrated by evaporation of solvent under reduced pressure.
  • l-Bromo-2-methoxyethane (0.067 ml) was added in one portion to tert-butyl 4-[4- [5 -amino-6-( 1 H-benzimidazol-2-yl)pyrazin-2-yl]pyrazol- 1 -yl]piperidine- 1 -carboxylate (300 mg) and caesium carbonate (424 mg) dissolved in DMF (5 ml). The mixture was stirred at 25°C for 16 hours.
  • Acetic acid 50 ml was added to tert-butyl 4-[4-[5-amino-6-[(2- aminophenyl)carbamoyl]pyrazin-2-yl]pyrazol-l-yl]piperidine-l-carboxylate (10.6 g) and the resulting solution was stirred at 90 0 C for 3 hours.
  • the reaction mixture was allowed to cool to ambient temperature under stirring over a period of 30 minutes, quenched with water, basified with a 2N aqueous solution of sodium hydroxide to pH 4.5 and extracted with ethyl acetate (200 x 3 ml).
  • Example 14 Using analogous procedures to those described in Example 14, the appropriate benzimidazole was reacted with an appropriate alkylating agent to give the compounds described in Table VII.
  • an appropriate alkylating agent As in Example 14, a N-tert-butoxycarbonyl (N-Boc) protecting group was employed. Where necessary, an O-tert-butoxy protecting group was employed on certain alkylating agents. Such protecting groups were removed using conventional treatment with trifluoroacetic acid. Unless otherwise stated, the required appropriate alkylating agents are commercially available. Table VII
  • Formaldehyde (0.028 ml) was added in one portion to a stirred solution of 3-[l-(2- methoxyethyl)benzimidazol-2-yl]-5-[l-(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (132 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 0 0 C under argon. The resulting solution was stirred at 0 0 C for 5 minutes. Sodium triacetoxyhydroborate (80 mg) was added and the mixture was stirred for 5 minutes at 25°C.
  • Formaldehyde (0.012 ml) was added in one portion to a stirred solution of 3 -(I - methylbenzimidazol-2-yl)-5-[ 1 -(piperidin-4-yl)pyrazol-4-yl]pyrazin-2-amine (52 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) at 0 0 C under argon. The resulting solution was stirred at 0 0 C for 5 minutes. Sodium triacetoxyhydroborate (35.3 mg) was added and the mixture was stirred for 5 minutes at 25°C. A solution of ammonia in methanol 7N (ImI) was added and the mixture was adsorbed on silica gel.
  • ImI ammonia in methanol 7N
  • the tert-butyl 4-(4-(5-amino-6-(3-aminopyridin-4-ylcarbamoyl)pyrazin-2-yl)pyrazol-l- yl)piperidine-l-carboxylate used as starting material was made as follows: Methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)pyrazol-4-yl)pyrazine-2- carboxylate (300 mg) and pyridine-3,4-diamine (407 mg) were dissolved into DMF (5 ml). Sodium methoxide (50 mg) was added to the mixture. The resulting mixture was stirred at 12O 0 C for 12 hours.
  • reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2x1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product.
  • reaction mixture was allowed to cool to room temperature under stirring over a period of 1 hour, quenched with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic phases were washed with water (3 x 30 ml), brine (1 x 20 ml), dried over magnesium sulfate and concentrated.
  • Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (334 mg), tert-butyl 4-[3-methyl-4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate (563 mg) and bis(triphenylphosphine) palladium (II) chloride (101 mg) and cesium fluoride (656 mg) in MeOH (11 mL) were degassed under vacuum and argon , stirred at 130 0 C for 20mn under microwave conditions. The mixture wac concentrated and the residue was dissolved in dichloromethane and filtered.
  • the resulting suspension was stirred at 25 0 C for overnight.
  • the reaction mixture was purified by preparative HPLC using a Waters X- Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford tert-butyl 4- [4-[5-amino-6-[(2-aminophenyl)carbamoyl]pyrazin-2-yl]-3-methyl-pyrazol- 1 - yl]piperidine-l-carboxylate (182 mg).

Abstract

L'invention porte sur des dérivés de pyrazine représentés par la Formule (I) ou sur un sel pharmaceutiquement acceptable de ceux-ci, chacun parmi G1, G2, le noyau A, R1, m, R2, R3, n et R4 ayant n'importe laquelle des significations définies auparavant dans la description ; sur des procédés permettant de les préparer, sur des compositions pharmaceutiques les contenant et sur leur utilisation dans la fabrication d'un médicament destiné à être utilisé pour le traitement de troubles liés à la prolifération cellulaire.
PCT/GB2008/050726 2007-08-21 2008-08-20 Dérivés de 2-pyrazinylbenzimidazole en tant qu'inhibiteurs des récepteurs tyrosine kinase WO2009024825A1 (fr)

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Publication number Priority date Publication date Assignee Title
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US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066629A2 (fr) * 2002-02-06 2003-08-14 Vertex Pharmaceuticals Incorporated Composes heteroaryles utiles en tant qu'inhibiteurs de gsk-3
WO2004084813A2 (fr) * 2003-03-21 2004-10-07 Smithkline Beecham Corporation Composes chimiques
WO2006063167A1 (fr) * 2004-12-08 2006-06-15 Smithkline Beecham Corporation 1h -pyrrolo[2,3-b]pyridines
WO2008038010A1 (fr) * 2006-09-30 2008-04-03 Vernalis (R & D) Limited Dérivés de pyrazine et leur utilisation thérapeutique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066629A2 (fr) * 2002-02-06 2003-08-14 Vertex Pharmaceuticals Incorporated Composes heteroaryles utiles en tant qu'inhibiteurs de gsk-3
WO2004084813A2 (fr) * 2003-03-21 2004-10-07 Smithkline Beecham Corporation Composes chimiques
WO2006063167A1 (fr) * 2004-12-08 2006-06-15 Smithkline Beecham Corporation 1h -pyrrolo[2,3-b]pyridines
WO2008038010A1 (fr) * 2006-09-30 2008-04-03 Vernalis (R & D) Limited Dérivés de pyrazine et leur utilisation thérapeutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M. J. BAMFORD ET AL.: "(1H-Imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: A novel class of potent MSK-1-inhibitors", BIOORG. MED. CHEM. LETT., vol. 15, 9 June 2005 (2005-06-09), pages 3402 - 3406, XP002500545 *

Cited By (82)

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US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9796664B2 (en) 2008-09-03 2017-10-24 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US8410112B2 (en) 2008-11-10 2013-04-02 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10961232B2 (en) 2008-12-19 2021-03-30 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
US9701674B2 (en) 2008-12-19 2017-07-11 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
US9365557B2 (en) 2008-12-19 2016-06-14 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
US10479784B2 (en) 2008-12-19 2019-11-19 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
US8841308B2 (en) 2008-12-19 2014-09-23 Vertex Pharmaceuticals Incorporated Pyrazin-2-amines useful as inhibitors of ATR kinase
JP2012532899A (ja) * 2009-07-15 2012-12-20 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 腫瘍および炎症性疾患の処置のためのアミノピリジン誘導体
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8962631B2 (en) 2010-05-12 2015-02-24 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9096584B2 (en) 2010-05-12 2015-08-04 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9062008B2 (en) 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8969356B2 (en) 2010-05-12 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8623869B2 (en) 2010-06-23 2014-01-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2012003338A1 (fr) 2010-07-01 2012-01-05 Takeda Pharmaceutical Company Limited Combinaison d'un inhibiteur de cmet et d'un anticorps dirigé contre hgf et/ou cmet
WO2012003912A1 (fr) 2010-07-05 2012-01-12 Merck Patent Gmbh Dérivés de bipyridyl utiles pour le traitement de maladies induites par des kinases
US10301323B2 (en) 2011-02-28 2019-05-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10981933B2 (en) 2011-02-28 2021-04-20 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9908899B2 (en) 2011-02-28 2018-03-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10280182B2 (en) 2011-02-28 2019-05-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9512143B2 (en) 2011-02-28 2016-12-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10526346B2 (en) 2011-02-28 2020-01-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8877759B2 (en) 2011-04-05 2014-11-04 Vertex Pharnaceuticals Incorporated Aminopyrazines as ATR kinase inhibitors
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US8822469B2 (en) 2011-06-22 2014-09-02 Vertex Pharmaceuticals Incorporated Pyrrolo[2,3-B]pyrazines useful as inhibitors of ATR kinase
US9096602B2 (en) 2011-06-22 2015-08-04 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-B]pyrazines as ATR kinase inhibitors
US8853217B2 (en) 2011-09-30 2014-10-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9035053B2 (en) 2011-09-30 2015-05-19 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US8846686B2 (en) 2011-09-30 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8765751B2 (en) 2011-09-30 2014-07-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
US9862709B2 (en) 2011-09-30 2018-01-09 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US10822331B2 (en) 2011-09-30 2020-11-03 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US10208027B2 (en) 2011-09-30 2019-02-19 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US8846918B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8846917B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841450B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841337B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841449B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8933103B2 (en) 2012-01-31 2015-01-13 Daiichi Sankyo Company, Limited Pyridone derivatives
WO2013115280A1 (fr) 2012-01-31 2013-08-08 第一三共株式会社 Dérivé de pyridone
KR20140117439A (ko) 2012-01-31 2014-10-07 다이이찌 산쿄 가부시키가이샤 피리돈 유도체들
US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US11110086B2 (en) 2012-04-05 2021-09-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
US8912198B2 (en) 2012-10-16 2014-12-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9650381B2 (en) 2012-12-07 2017-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11117900B2 (en) 2012-12-07 2021-09-14 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10392391B2 (en) 2012-12-07 2019-08-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10787452B2 (en) 2012-12-07 2020-09-29 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11370798B2 (en) 2012-12-07 2022-06-28 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9718827B2 (en) 2012-12-07 2017-08-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9657008B2 (en) 2013-01-23 2017-05-23 Astrazeneca Ab Chemical compounds
US9156831B2 (en) 2013-01-23 2015-10-13 Astrazeneca Ab Chemical compounds
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10428028B2 (en) 2013-03-15 2019-10-01 Biomarin Pharmaceutical Inc. HDAC inhibitors
WO2015077375A1 (fr) 2013-11-20 2015-05-28 Signalchem Lifesciences Corp. Dérivés de quinazoline servant d'inhibiteurs des kinases de la famille tam
WO2015081257A2 (fr) 2013-11-27 2015-06-04 Signalchem Lifesciences Corporation Dérivés d'aminopyridine utilisés comme inhibiteurs de kinases de la famille tam
US10815239B2 (en) 2013-12-06 2020-10-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11485739B2 (en) 2013-12-06 2022-11-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10160760B2 (en) 2013-12-06 2018-12-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10093676B2 (en) 2014-06-05 2018-10-09 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US10800781B2 (en) 2014-06-05 2020-10-13 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US11179394B2 (en) 2014-06-17 2021-11-23 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of Chk1 and ATR inhibitors
US11208403B2 (en) 2014-07-07 2021-12-28 Daiichi Sankyo Company, Limited Pyridone derivatives having tetrahydropyranylmethyl groups
US10442797B2 (en) 2014-07-07 2019-10-15 Daiichi Sankyo Company, Limited Pyridone derivatives having tetrahydropyranylmethyl groups
EP3868757A1 (fr) 2014-07-07 2021-08-25 Daiichi Sankyo Company, Limited Dérivés de la pyridone ayant le groupe tétrahydropyranylmethyl
KR20170029495A (ko) 2014-07-07 2017-03-15 다이이찌 산쿄 가부시키가이샤 테트라하이드로피라닐메틸기를 갖는 피리돈 유도체
WO2016091891A1 (fr) 2014-12-09 2016-06-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticorps monoclonaux humains contre axl
WO2016135066A1 (fr) 2015-02-26 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Protéines de fusion et anticorps comprenant celles-ci pour la promotion de l'apoptose
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors
WO2017146236A1 (fr) 2016-02-26 2017-08-31 小野薬品工業株式会社 Médicament pour le traitement du cancer caractérisé par l'administration d'une association d'un inhibiteur de l'axl et d'un inhibiteur de point de contrôle immunitaire
WO2019039525A1 (fr) 2017-08-23 2019-02-28 小野薬品工業株式会社 Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d'axl en tant que principe actif
WO2019074116A1 (fr) 2017-10-13 2019-04-18 小野薬品工業株式会社 Agent thérapeutique pour cancers solides, qui contient un inhibiteur d'axl en tant que principe actif

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